7
ARCH. SOC. CANAR. OFTAL., 2019; 30: 7-14 ARTÍCULO ORIGINAL
Análisis de la capa de fibras nerviosas
de la retina con tomografía de
coherencia óptica en niños con
migraña
Analysis of the retinal nerve fiber layer in children
with migraine using optic coherence tomography
FERNÁNDEZ MONTALVO L1, MENGUAL VERDÚ E1, FONT JULIÁ E1,
HUESO ABANCENS JR1, SEMPERE ORTELLS JM2, CARRATALÁ MARCO F3
RESUMEN
Objetivo: El propósito de este estudio fue encontrar anomalías estructurales en la capa de fibras
nerviosas de la retina (CFNR) de niños y adolescentes con migraña.
Métodos: Este estudio incluyó a 50 pacientes en el grupo migraña, 25 con aura visual y 25 sin
aura, y 25 sujetos en el grupo control. Se usó la tomografía de coherencia óptica de dominio
espectral para medir y comparar el grosor de la CFNR entre los grupos migraña y control.
Resultado: Hubo una diferencia significativa en el grosor medio de la CFNR (ojo derecho,
OD = p < 0,013; ojo izquierdo, OI = < 0,019). y en los cuadrantes nasal (OD = p < 0,001;
OI = p < 0,001) y temporal (OD = p < 0,001; OI = p < 0,001) en el grupo migraña en
comparación con el control. Al comparar el subgrupo migraña con aura con el subgrupo
migraña sin aura se encontró una diferencia estadísticamente significativa en el grosor de la
CFNR en cuadrantes superior (OD = p < 0,004; OI = p < 0,003), temporal (OD = p < 0,008;
OI = p < 0,001) y nasal (OD = p < 0,001; OI = p < 0,001).
Conclusiones: Este estudio sugiere que la migraña provoca una reducción del grosor de la
CFNR peripapilar.
Palabras clave: Adolescentes. Niños. Migraña. OCT. CFNR.
ABSTRACT
Aim: The purpose of this study was to find structural abnormalities in the retinal nerve fiber
layer (RNFL) of children and adolescents with migraine
Methods: This study included 50 patients with migraine , 25 with visual aura and 25 without,
and a control group of 25 subjects. Spectral domain optic coherence tomography was used
to measure and compare RNFL thickness between the migraine and control groups.
1 Ophthalmology Department, San Juan University Hospital, Alicante, Spain.
2 Biotechnology Department, University of Alicante, Alicante, Spain.
3 Neuropaediatric Department, University Hospital San Juan de Alicante, Alicante, Spain.
Correspondencia:
Lorena Fernández Montalvo
Ophthalmology Department
Ctra. Nnal. 332, Alacant-Valencia, s/n, 03550 Sant Joan d’Alacant, Alicante
lorenafmontalvo@gmail.com
FERNÁNDEZ MONTALVO L, et al.
8 ARCH. SOC. CANAR. OFTAL., 2019; 30: 7-14
BACKGROUND
Migraine headache frequently occurs in
children and adolescents and is one of the
most common diseases of childhood with
a prevalence of 9.1 % (1). In almost 30%
of people with migraine, the headache is
preceded by a wide range of neurological
symptoms (visual, motor, or somatosensory)
known as aura, and which can last between 5
to 60 minutes or sometimes for several days
(2,3). Migraine can be clinically subdivided
into two major groups: migraine with aura
(MWA) and migraine without aura (MWoA)
(4). It differs from migraine in adults in
that the headache is bilateral, gastrointesti-nal
symptoms are more prominent and the
attacks may beshorter and last between 1
and 72 hours. Due to these features, itis also
likely to be under-diagnosed (3,5,6).
The pathogenesis of migraine remains un-clear.
Focal reduction of blood flow reported
in migraine attacks, particularly in MWA,
most commonly starts in posterior circula-tion,
that is to say, within the vascular terri-tory
supplied by the vertebrobasilar system
(7). Rarely, hypoperfusion arises from other
parts of the brain in cluding the retina (6-8).
Retinal strokes caused by retinal artery occlu-sions
have been reported in migraine patients
(8,11). Although the vasoconstriction of ce-rebral
and retinal blood vessels is a transient
phenomenon, the chronic nature of migraines
could lead to permanent structural abnor-malities
through less intense hypoperfusion
phenomena (10,12-14). In one study by Kara
et al. in which Doppler ultrasound was used
to demonstrate retinal vascular changes and
perfusion on adult migraine patients, they
found that the resistance in the central retinal
artery and posterior ciliary artery was higher
in migraine patients than in the control group
during intercritic periods (15).
An alteration of the quality of perfusion in
the optic nerve head or in the retina may lead
to ganglion cell death in migraine patients
(16,17). Retinal nerve fiber layer (RNFL)
thickness measurements can be used as an
index to assess ganglion cell and retinal ner-ve
fiber damages.The aim of this study was
to compare the RNFL thickness in the eyes
of migrainous children and adolescents with
healthy controls using spectral-domain opti-cal
coherence tomography (OCT).
METHODS
This was a prospective observational stu-dy
conducted in the Ophthalmology Service
of the University Hospital San Juan de Ali-cante,
Alicante, Spain. We studied 100 eyes
of 50 consecutive patients (15 male, 35 fe-male;
mean age = 9.5 years-old (5-15 yo.
range) with migraine using the criteria of the
Headache International Society (4). All the
patients were referred from the Neuropaedia-trics
Department of the same hospital. The
50 patients, all Caucasian, were divided into
two subgroups: 25 with MWA (10 male and
15 female; mean age = 9.16 yo; range = 5-15
yo.) and 25 MWoA (6 male and 19 female ;
mean age = 9.84 yo.; range = 5-15 yo.). The
control group consisted of 25 healthy controls
(10 male and 15 female; mean age = 9.9 yo.;
range = 5-15 yo.). We excluded patients with
any prophylactic treatment to avoid possible
effects of these drugs on retinal nerve fiber
layer thickness.
Written informed consent was obtained
from the parents of participating minors. The
project was approved by the Research Ethics
Results: There was a significant reduction in the average RNFL thickness (oculus dexter,
OD = p < 0.013; oculus sinister, OS = < 0.019) and that of the nasal (OD = p < 0.001;
OS = p < 0.001) and temporal quadrants (OD = p < 0.001; OS = p < 0.001) in the migraine
group compared to those of the control one.. Also comparing the migraine with aura subgroup
to the migraine without aura subgroup , there was a statistically significant difference in
RNFL thickness parameters according to the superior (OD = p < 0.004; OS = p < 0.003), tem-poral
(OD = p < 0.008; OS = p < 0.001) and nasal sectors (OD = p < 0.001; OS = p < 0.001).
Conclusions: This study suggests that migraine leads to a reduction in the peripapillary RNFL
thickness.
Keywords: Adolescent, children, migraine, OCT, RNFL
Análisis de la capa de fibras nerviosas de la retina con tomografía de coherencia óptica en niños con migraña
ARCH. SOC. CANAR. OFTAL., 2019; 30: 7-14 9
Board at The University Hospital San Juan de
Alicante, and conducted in accordance with
the Tenets of Helsinki.
All patients underwent complete neuro-logical
and paediatric exam which excluded
any other origin of the headache than the
migraine. The ophthalmologic exam inclu-ded
the following tests: best-corrected vi-sual
acuity (using Snellen charts), slit-lamp
biomicroscopy, dilated funduscopic exami-nation
with a 90-diopter lens, axial length
(AL), and manifest refraction and cyclople-gic
refraction after pupillary dilation with
one drop of cyclopentolate 1%. All children
with a spherical equivalent more myopic than
–2.00 diopter and more hyperopic than +3.00
were excluded. Ocular axial lengths was
measured using an corneal biometry device
(OcuScan® RxP; Alcon, Forth Worth, Texas,
USA). Patients with a history of intraocular
surgery, retinal or neurological disease, nys-tagmus,
glaucoma, laser treatment, or cata-ract
and patients not sufficiently cooperative
to undergo an optical coherence tomography
examination were excluded. Each subject
was imaged three times with SD-OCT (Top-con
3D OCT-2000, Japan, protocol 3D-Disc
cube) to evaluate peripapillary RNFL thick-ness
and the mean values were recorded. All
scans were performed by the same operator
through dilated pupils. An internal fixation
target was also used in all scans with the re-altime
eye tracking system to adjust for eye
motion. SD-OCT measurements were taken
at the same time of the day to minimize the
effects of diurnal variation.
The SD-OCT scan protocol used to evalua-te
RNFLwas calculated by the optic disc cube
512 x 128 (128 horizontal scan lines compri-sed
of 512 A-scans, in a 6 x 6 mm area) with a
maximum scan velocity of 50.000 axial scans/
second. Parameters including average RNFL
thickness in four quadrants were generated
automatically in the analysis report. The ave-rage
and four-quadrant RNFL thickness data
–temporal, superior, nasal and inferior– were
collected and compared insidethe migrai-ne
group –that is to say, MWA group versus
MWoA group. Then, combined data from the
migraine group (MWA+MWoA) were also
compared to the control group. In addition,
we calculated the correlations among average
RNFL thickness and age, sex and the migrai-ne
duration from diagnosis (fig. 1).
The statistical analysis was perfomed
using the Statistical Package for Social Scien-ces
(SPSS) program version 20.0, for Win-dows
(SPSS, Chicago, IL, USA). Data were
reported as the mean ± standard deviation
(SD). The normality of the distribution for all
variables was assessed by the Kolmogorov-
Smirnov test. Student’s t-test was used for the
comparison of normally distributed variables
and Mann-Whitney U test was used for non-parametric
variables between the two groups.
Relationships between variables were analy-zed
by Pearson or Spearman correlation
analysis according to the distribution type of
the variables. Differences were considered
significant if theyexceed the 95% confidence
interval.
RESULTS
According to the demographic features,
there were no statistically significant diffe-rences
between patients with migraine and
the control group in sex and age. Within the
migraine group, 25 had MWA and 25 MWoA.
No significant difference was found between
the two migraine subgroups in demographic
features and clinical characteristics of heada-che
(table 1).
Average RNFL thickness was 92.60 ±
6.64 μm in OD and 92.44 ± 5.97 μm in OS of
the MWA subgroup; the difference was statis-tically
insignificant (p 0.929). There were no
statistically significant differences in average
RNFL thickness of the right and left eyes in
the MWoA subgroup (OD = 104.56 ± 7.84
vs OS = 104.72 ± 7.51 μm ; p 0.942). In the
same way, there were no statistically signifi-cant
differences in average RNFL thickness
Fig. 1: Materials
and methods.
MWA (Migraine
with Aura), MWoA
(Migraine without
Aura), RNFL
(Retinal Nerve
Fiber Layer), AL
(Axial length).
FERNÁNDEZ MONTALVO L, et al.
10 ARCH. SOC. CANAR. OFTAL., 2019; 30: 7-14
of the right and left eyes in the control group
(OD = 99.92 ± 6.3 vs OS = 100.84 ± 7.1 μm;
p 0.689).
The migraine group (MWA+MWoA)
compared to the control group showed a sta-tistically
significant difference in RNFL thic-kness
parameters according to the temporal
(OD = 77.42 ± 10.6 vs 121.64 ± 15.2 μm;
p < 0.01. OS = 75.22 ± 13.4 vs 125.6 ± 16.5;
p < 0.01) and inferior (OD = 120.11 ± 17.1 vs
80.92 ± 17.12 μm; p < .01. OS = 126.34 ± 13.7
vs 80.68 ± 21.37; p < 0.01) sectors.There were
no statistically significant differences in the
other RNFL thickness parameters and axial
length between the two groups (table II).
The MWA subgroup and the MWoA
subgroup showed a statistically signifi-cant
difference in average RNFL thickness
(OD = 92.6 ± 6.64 vs 104.5 ± 7.84 μm; p < 0.01.
OS = 92.44 ± 5.97 vs 104.72 ± 7.5; p < 0.001) and
according to the superior (OD = 115.9 ± 15.9 vs
128.64 ± 13.9 μm; p 0.004. OS = 113.0 ± 19.9
vs 123.36 ± 13.64; p < 0.01), inferior
(OD = 111.16 ± 15.33 vs 127.04 ± 10.01 μm;
p < 0.01. OS = 117.68 ± 10.59 vs 135 ± 10.68;
p < 0.01) and nasal (OD = 68.24 ± 12.3 vs
82.0 ± 12 μm; p < 0.01. OD = 69.2 ± 16.82 vs
83.88 ± 10.03 μm; p 0.001) sectors. There
were no statistically significant differences in
the other RNFL thickness parameters and axial
length between the MWA subgroup and the
MWoA subgroup (table III).
Average RNFL thickness was 97.72 in
boys and 98.88 in girls. There were no sta-tistically
significant differences between the
sexes. There was a significant correlation
between age and average RNFL thickness
for both sexes (r 0.245; p 0.014). Therefore,
greater RNFL thickness was detected with in-creasing
patient age (fig. 2).
DISCUSSION
RNFL thickness measurements can be
used as a mark in order to assess the ganglion
cell damages (16). As a result of ganglion cell
damage, a reduction in the thickness of this
layer can be expected. OCT is a non-invasive,
non-contact imaging technique that renders
in vivo cross sectional view of the retina. It
enables quantitative assessment of the RNFL
thickness around the optic nerve head and
Table I: Clinical characteristics of migraine subgroups
Variable Migraine with aura Migraine without aura p-value*
Diagnosis time (year) 1.88 ± 1.22 2.36 ± 1.06 0.704
Frequency of attacks (month) 2.8 ± 1.6 3.1 ± 1.6 0.694
Unilateral 16 14 0.314
Bilateral 9 12 0.314
Table II: Comparison of retinal nerve fiber layer (RNFL) thickness in
migraine and control groups
Variable Migraine (n=50)a Control (n=25)a p-value*
OD AL (mm) 22,95 ± 0.8 23,10 ± 0.8 0.457
OD RNFL average, ʯm 98.92 ± 9.3 99.92 ± 6.3 0.631
OD RNFL superior, ʯm 122.22. ± 16.1 122.80 ± 10.1 0.870
OD RNFL inferior, ʯm 120.11 ± 17.1 80.92 ± 17.12 0.001*
OD RNFL temporal, ʯm 77.42 ± 10.6 121.64 ± 15.2 0.001*
OD RNFL nasal, ʯm 75.56 ± 12.8 76.4 ± 7.6 0.763
OS AL (mm) 22,91 ± 0.8 23,10 ± 0.8 0.239
OS RNFL average, ʯm 98.58 ± 9.14 100.68 ± 7.1 0.317
OS RNFL superior, ʯm 118.18 ± 18 121.76 ± 12.05 0.366
OS RNFL inferior, ʯm 126.34 ± 13.7 80.68 ± 21.37 <0.001*
OS RNFL temporal, ʯm 75.22 ± 13.4 125.6 ± 16.55 <0.001*
OS RNFL nasal, ʯm 76.54 ± 15.6 77.04 ± 8.48 <0.882
OD RNFL: Right eye Retinal nerve fiber layer in right eye; OS RNFL: Left eye Retinal nerve
fiber layer in left eye.*p < 0.05 a Values are mean ± SD.
Table III: Comparison of retinal nerve fiber layer (RNFL) in migraine
subgroups
Variable MWA (n=25)a MWoA(n=25)a p-value*
OD AL (mm) 22.97 ± 0.82 22.91 ± 0.81 0.817
OD RNFL average, ʯm 92.6 ± 6.64 104.5 ± 7.84 <0.001*
OD RNFL superior, ʯm 115.9 ± 15.9 128.64 ± 13.9 0.004*
OD RNFL inferior, ʯm 111.16 ± 15.3 127 ± 10.01 0.001*
OD RNFL temporal, ʯm 75.08 ± 8.8 79.84 ± 11.9 0.115
OD RNFL nasal, ʯm 68.24 ± 12.3 82 ± 12 <0.001*
OS AL (mm) 22.9 ± 0.8 22.8 0.692
OS RNFL average, ʯm 92.44 ± 5.97 104,72 ± 7.5 <0.001*
OS RNFL superior, ʯm 113.0 ± 19.9 123.36 ± 13.64 0.037*
OS RNFL inferior, ʯm 117.68 ± 10.59 135.0 ± 10.68 0.001*
OS RNFL temporal, ʯm 72.52 ± 10.41 77.9 ± 15.62 <0.157
OS RNFL nasal, ʯm 69.2 ± 16.82 83.88 ± 10.03 <0.001*
OD RNFL: Right eye Retinal nerve fiber layer in right eye; OS RNFL: Left eye Retinal nerve
fiber layer in left eye. * p < 0.05a Values are mean ± SD.
Análisis de la capa de fibras nerviosas de la retina con tomografía de coherencia óptica en niños con migraña
ARCH. SOC. CANAR. OFTAL., 2019; 30: 7-14 11
is considered a reliable tool for the diagno-sis
and follow-up of glaucoma and neuroo-phthalmic
diseases (16,17).
As a result of present study, a statistically
significant reduction in RNFL thickness mea-surements
of migraine group was detected.
The inferior and temporal quadrant RNFL
thickness were found to be significantly thin-ner
in the children with migraine compared
with that in the control group.
As far as we know, only Nalcacioglu et
al. measured RNFL thickness in 40 pediatric
migraine patients and compare the values
with 40 healthy subjects using SD-OCT; they
determined no reduction in the RNFL thick-ness
in any quadrant, and they asserted that
migraine had no effect on RNFL (18).
Previous studies in adults using OCT have
provided evidence of reduced RNFL thick-ness
in migraine patients, but the results are
not completely consistent.
In a study conducted by Martinez et al.,
RNFL thickness was found to be significantly
thinner in the temporal quadrant of migraine
patients compared to the control group (19).
In another study carried out by Sorkhabi et
al. RNFL thickness was only significantly
thinner in nasal quadrant in migraine patients
compared to the control group (20). Also De-mircan
et al. found that the mean RNFL thic-kness
for nasal and inferior sectors was signi-ficantly
thinner in the migraine group than in
the control group (21). In another study con-ducted
by Yulek et al., average RNFL thick-ness
in the migraine group was found to be
thinner compared to the control group (22).
Colak et al. revealed a reduction in the avera-ge
RNFL thickness in adult migraine patients
compared with that in the control group. Si-milarly,
superior and inferior quadrant RNFL
thicknesses were significantly lower as well
(23). A recent meta-analysis by Feng et al.,
showed that RFNL thickness decreased in all
quadrants in migraine patients compared with
the healthy control group (24).
Opposed to the findings of above stu-dies,
Tan et al.reported that there was no sta-tistically
significant difference in RNFL thic-kness
by using laser polarimetry (25).
In our study, while there was no statisti-cally
significant difference in the average,
superior and nasal quadrant RNFL thickness
measurements between the groups, inferior
and temporal quadrant RNFL thickness were
found to be significantly thinner in the chil-dren
with migraine compared with that in the
control group.
Gipponi et al. compared female adult pa-tients
with migraine to healthy women, and
determined that superior RNFL quadrant
was significantly reduced only in migraine
patients with aura but not in those without
aura (26). Unlike their results, Demircan et
al. found no differences between RNFL in
migraine with aura and migraine without
aura subgroups (21). In our study, when the
patients were evaluated as subgroups of mi-graine
with aura and without aura, there was
a significant thinning of the average RNFL
thickness parameters and according to the su-perior,
inferior and nasal sectors in migraine
patients with aura, but no significant differen-ces
in in the other RNFL thickness measure-ments.
In accordance with Sorkhabi et al., De-mircan
et al. and Gipponi et al, we report that
RFNL thickness is independent of headache
duration from diagnosis in children with
migraine (20,21,26). Besides, there were no
statistically significant differences in RNFL
thickness between sexes. However, there
was asignificant correlation between age and
RFNL thickness for both sexes (the greater
the age, the more RNFL thickness).
Unlike other studies, we only measu-red
RFNL thickness in migraine patients
with and without aura and we compared the
results with healthy controls. Attacks of mi-graine
may be linked to hypoperfusion in
the retina and optic nerve. The choroid, the
vascular layer of the eye, is responsible for
most of the ocular blood supply and is vital
for the maintainance of the outer retina (27).
Fig. 2.
FERNÁNDEZ MONTALVO L, et al.
12 ARCH. SOC. CANAR. OFTAL., 2019; 30: 7-14
Migraine is known to reduce blood flow at
the level of the central retinal and posterior
ciliary arteries. Demircan et al. and Ekinci et
al. report a thinning of the choroid layer in
adult migraine patients (21,28). Nevertheless,
there are discrepancies between the different
studies in relation to choroidal thickness du-ring
the migraine attack period. Dadaci et al.
and Karalezli et al. reported an increased cho-roidal
thickness during the migraine attack
period (28,30) contrary to Dervisogullari et
al. and Zengin et al., who reported a reduc-tion
in choroidal thickness during the migrai-ne
attack period in MWA and MWoA groups
(31,32). These differencescould be explai-ned
by the fact that both migraine subgroups
switch from hypoperfusion to hyperperfusion
during their course.
On the other hand, athinning in the RNFL
thickness has been reported in adult migrai-ne
patients probably due to retinal ischemia.
Contrary to the choroidal vessels, the intrao-cular
portion of the retinal vessels has no au-tonomic
innervation. The anterior part of the
optic nerve is supplied by the short posterior
ciliary arteries and choroidal vessels, while
the superficial layer of the optic nerve head is
supplied by small branches originating from
the central retinal artery. It maybe that an
alteration in blood flow in the anterior optic
nerve head can cause hypoxic injury, resul-ting
in ganglion cell death.
Although the involved quadrants were di-fferent
in the present study and previous stu-dies,
they align on the finding that migraine
can result in focal decrease in cerebral blood
flow, and partirculary in retinal circulation.
Regarding the significant difference
of RNFL thickness in inferior and tem-poral
quadrants between migraine group
(MWA+MWoA) and the control group, it
might be hypothesized that retinal infarctions
due to occlusion of retinal arterybranches
have a role in migraine. To confirm this, lar-ger
studies are required.
Interestingly, RNFL thickness measu-rement
could be a useful technique through
which to evaluate the severity and the evo-lution
of migraine, and perhaps to study
whether prophylactic treatment could reduce
retinal abnormalities seen in migrainous pa-tients.
OCT-SD is a harmless exam that could
be used in children and repeated for evalua-tion
of headache progression.
The main limitation of our study is the
small number of cases. However, the number
of patients per group was comparable to those
conducted in studies with adults.
In conclusion, the peripapillary RNFL
was significantly thinner in children with mi-graine
than in the healthy control subjects,
particularly in the migrainous with aura.
Our study suggests that in children, migraine
leads to a thinning of the peripapillary RNFL
thickness. Such thinning is thought to be re-lated
to a progressive loss of ganglion cells
and axons caused by the chronic nature of
headache disorders. Our results confirm these
data, and suggest that this may happen due to
pathogenesis of migraine, rather than in rela-tion
to the natural aging process.
Future studies could also identify whether
appropriate prophylactic treatment which re-duces
the frequency of attacks and duration
of the headache may prevent thinning the
RNFL thickness in children with migraine.
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